Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases have been reported to be involved in tumor cell invasion and metastasis. Dissemination of malignant cells in acute myeloid leukemia (AML) may be mediated by similar mechanisms. Here, we report, that the t(15/17)+ acute promyelocytic leukemia (APL) cell line NB4 constitutively expresses and releases the proenzyme form of matrix metalloproteinase-9 (MMP-9, 92 kDa type IV collagenase/gelatinase, gelatinase B), as well as tissue inhibitor of metalloproteinases-1 (TIMP-1). Both proteins were identified by N-terminal amino acid sequence analysis after purification using gelatin Sepharose affinity chromatography. Whereas 12-O-tetradecanoylphorbol-13 acetate (TPA) increased both MMP-9 and TIMP-1 mRNA levels, tumor necrosis factor-alpha (TNF-alpha) stimulated only MMP-9 gene expression in a dose- and time-dependent manner. Neutralizing monoclonal antibodies (MoABs) to TNF-alpha (anti-TNF-alpha) decreased the constitutive and TPA-dependent expression of MMP-9 but did not influence TIMP-1 expression, either in unstimulated or in TPA-treated NB4 cells. FACS analyses showed that NB4 cells express both TNF receptor 1 (TNF-R1) and TNF-R2 to a similar extent. Blocking MoABs against TNF-R 1 (anti-TNF-R1) decreased the constitutive expression of MMP-9, whereas anti-TNF-R2 had almost no effect. Our results show, that in NB4 cells the expression of MMP-9 but not of TIMP-1 is maintained by autocrine stimulation with TNF-alpha. Thus, leukemic cells may be enabled to leave the bone marrow and infiltrate peripheral tissues by a dysfunction in the regulation of the MMP-9:TIMP-1 equilibrium, possibly triggered through autostimulation by TNF-alpha.
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PMID:Autocrine regulation of matrix metalloproteinase-9 gene expression and secretion by tumor necrosis factor-alpha (TNF-alpha) in NB4 leukemic cells: specific involvement of TNF receptor type 1. 966 1

In order to investigate the regulatory role of only one endometrial cell type on trophoblastic invasion, we explored the effects of culture medium conditioned by in vitro decidualised stromal cells (DCM) and of insulin-like growth factor binding protein-1 (IGFBP-1, the main secretory product of decidual cells) on the trophoblastic secretion of gelatinases and tissue inhibitor of metalloproteinases (TIMP-1). First trimester cytotrophoblastic cells (CTB) were obtained from abortions and cultured in vitro in presence or absence of DCM or IGFBP-1. Secreted gelatinases were analysed in the culture supernatants by zymography and by measurements of the total gelatinolytic activity. Tissue inhibitor of metalloproteinases (TIMP-1) was measured by a commercially available immunoassay. DCM inhibited the total gelatinolytic activity of CTB but increased trophoblastic MMP-9 and TIMP-1. In contrast, IGFBP-1 increased the total gelatinolytic activity and TIMP-1 and had no effect on MMP-2 and MMP-9. We conclude that a factor secreted by decidual cells (possibly TGFbeta) inhibits the total gelatinolytic activity of trophoblast by increasing TIMP-1 but other factors, as yet unidentified, increase MMP-2 and MMP-9 to an extent which does not shift the equilibrium between the gelatinases and TIMP-1 in favour of the gelatinases. In contrast to DCM, IGFBP-1 increases the total gelatinolytic activity probably by stimulating another gelatinase (stromelysin-1?) as MMP-2 and MMP 9 are unchanged by IGFBP-1. The possibility of an integrin mediated effect of IGFBP-1 on CTB is discussed.
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PMID:Involvement of trophoblast in embryo implantation: regulation by paracrine factors. 978 60

We compared the association constants of tissue inhibitor of metalloproteinases (TIMP)-3 with various matrix metalloproteinases with those for TIMP-1 and TIMP-2 using a continuous assay. TIMP-3 behaved more like TIMP-2 than TIMP-1, showing rapid association with gelatinases A and B. Experiments with the N-terminal domain of gelatinase A, the isolated C-terminal domain, or an inactive progelatinase A mutant showed that the hemopexin domain of gelatinase A makes an important contribution to the interaction with TIMP-3. The exchange of portions of the gelatinase A hemopexin domain with that of stromelysin revealed that residues 568-631 of gelatinase A were required for rapid association with TIMP-3. The N-terminal domain of gelatinase B alone also showed slower association with TIMP-3, again implying significant C-domain interactions. The isolation of complexes between TIMP-3 and progelatinases A and B on gelatin-agarose demonstrated that TIMP-3 binds to both proenzymes. We analyzed the effect of various polyanions on the inhibitory activity of TIMP-3 in our soluble assay. The association rate was increased by dextran sulfate, heparin, and heparan sulfate, but not by dermatan sulfate or hyaluronic acid. Because TIMP-3 is sequestered in the extracellular matrix, the presence of certain heparan sulfate proteoglycans could enhance its inhibitory capacity.
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PMID:Human tissue inhibitor of metalloproteinases 3 interacts with both the N- and C-terminal domains of gelatinases A and B. Regulation by polyanions. 1019 61

Tissue from 54 histologically-identified basal cell carcinomas of the skin was obtained at surgery and assayed using a combination of functional and immunochemical procedures for matrix metalloproteinases (MMPs) with collagenolytic activity and for MMPs with gelatinolytic activity. Collagenolytic enzymes included MMP-1 (interstitial collagenase), MMP-8 (neutrophil collagenase) and MMP-13 (collagenase-3). Gelatinolytic enzymes included MMP-2 (72-kDa gelatinase A/type IV collagenase) and MMP-9 (92-kDa gelatinase B/type IV collagenase). Inhibitors of MMP activity including tissue inhibitor of metalloproteinases-1 and -2 (TIMP-1 and TIMP-2) were also assessed. All three collagenases and both gelatinases were detected immunochemically. MMP-1 appeared to be responsible for most of the functional collagenolytic activity while gelatinolytic activity reflected both MMP-2 and MMP-9. MMP inhibitor activity was also present, and appeared, based on immunochemical procedures, to reflect the presence of TIMP-1 but not TIMP-2. As a group, tumours identified as having aggressive-growth histologic patterns were not distinguishable from basal cell carcinomas with less aggressive-growth histologic patterns. In normal skin, the same MMPs were detected by immunochemical means. However, only low to undetectable levels of collagenolytic and gelatinolytic activities were present. In contrast, MMP inhibitor activity was comparable to that seen in tumour tissue. In previous studies we have shown that exposure of normal skin to epidermal growth factor in organ culture induces MMP up-regulation and activation. This treatment concomitantly induces stromal invasion by the epithelium (Varani et al (1995) Am J Pathol 146: 210-217; Zeigler et al (1996b) Invasion Metastasis 16: 11-18). Taken together with these previous data, the present findings allow us to conclude that the same profile of MMP/MMP inhibitors that is associated with stromal invasion in the organ culture model is expressed endogenously in basal cell carcinomas of skin.
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PMID:Collagenolytic and gelatinolytic matrix metalloproteinases and their inhibitors in basal cell carcinoma of skin: comparison with normal skin. 1068 80

Wound extracellular matrix is a key regulator of cell adhesion, migration, proliferation, and differentiation during cutaneous repair. The amount and organization of normal wound extracellular matrix are determined by a dynamic balance among overall matrix synthesis, deposition, and degradation. Matrix metalloproteinases (MMPs) are one family of structurally related enzymes that have the collective ability to degrade nearly all extracellular matrix components. The MMPs are broadly categorized into collagenases, gelatinases, stromelysins, and membrane-type MMPs by their substrate specificity. The aim of this study was to characterize the temporal changes in mRNA profiles for rat collagenase [matrix metalloproteinase-1 (MMP-1)], gelatinase A (MMP-2), matrilysin (MMP-7), gelatinase B (MMP-9), and membrane type 1-MMP (MT1-MMP), as well as tissue inhibitor of metalloproteinases-1 (TIMP-1), TIMP-2, and TIMP-3 during the inflammatory, granulation, and early remodeling phases of excisional skin repair. Eight full-thickness skin wounds were made on the backs of each rat (7-mm2 wounds; 16 rats; n = 128 wounds). Two animals at a time were reanesthetized, and all eight wounds on each animal were excised at 12 and 24 hours and at 2, 3, 5, 7, 10, and 14 days after injury. Six wounds from each animal were excised for RNA isolation, whereas two wounds were excised for histology. Controls consisted of nonwounded skin from identical locations in four animals. Total RNA from each time point was isolated and relative mRNA quantitation performed by using reduced-cycle reverse transcription-polymerase chain reaction. Correct polymerase chain reaction product amplification was confirmed by probing the blotted polymerase chain reaction product with a 32P-labeled oligonucleotide specific for a given MMP or TIMP. We demonstrated that the majority of MMP and TIMP mRNA induction and peak expression coincided temporally with the well-characterized inflammatory and granulation stages of repair. In conclusion, there is a distinct pattern of MMP and TIMP expression during normal excisional wound repair.
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PMID:Differential expression of matrix metalloproteinases and their tissue-derived inhibitors in cutaneous wound repair. 1088 58

Chlamydia pneumoniae, an intracellular Gram-negative respiratory bacterium, and macrophages are present in inflammatory tissue sites such as atherosclerotic lesions, where abnormal degradation of the extracellular matrix takes place. To evaluate the potential of C pneumoniae for participation in matrix destruction, we studied the effect of this bacterium on the production of 3 matrix-degrading metalloproteinases, 92-kDa gelatinase, interstitial collagenase-1, and stromelysin-1, and their natural inhibitor TIMP-1 (tissue inhibitor of metalloproteinases-1) by human monocyte-derived macrophages differentiated in vitro. Spontaneous production of collagenase and stromelysin by these cells was minimal and was not influenced by C pneumoniae. In contrast, the cells secreted substantial basal quantities of 92-kDa gelatinase, the secretion of which was stimulated (on average, 2.5-fold) by C pneumoniae. C pneumoniae regulated the expression of 92-kDa gelatinase by macrophages at the pretranslational level. Macrophages secreted only small quantities of TIMP-1. The chlamydial proteins Omp2, MOMP, and HSP60 were also found to participate in the induction of 92-kDa gelatinase by C pneumoniae. Denaturation of chlamydial proteins by boiling reduced 92-kDa gelatinase secretion only partially (by 35%), suggesting that the heat-stabile lipopolysaccharide molecules also stimulate secretion of the enzyme. The results show that production of 92-kDa gelatinase by human macrophages is selectively upregulated by C pneumoniae, which suggests that these bacteria, when present in a macrophage-containing inflammatory environment, actively participate in the destruction of the extracellular matrix.
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PMID:Chlamydia pneumoniae proteins induce secretion of the 92-kDa gelatinase by human monocyte- derived macrophages. 1114 52

Glycosylation influences the specific activities of serine proteases including tissue-type plasminogen activator and plasmin which act together in a ternary complex with fibrin. Serine proteases and matrix metalloproteinases (MMPs), including gelatinase B, participate in a protease cascade to remodel the extracellular matrix. In addition to the recognition and targeting functions of carbohydrates and the fact that they confer protease resistance on glycoproteins, oligosaccharides may extend particular protein domains of matrix remodelling enzymes and fine-control their activities within the context of the extracellular matrix. For example, the sialic acids of gelatinase B influence the catalytic activity of this enzyme in a complex with the tissue inhibitor of metalloproteinases-1 (TIMP-1).
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PMID:Matrix remodelling enzymes, the protease cascade and glycosylation. 1168 91

The gelatinases are a subgroup of the matrix metalloproteinase family. The interaction of their C-terminal hemopexin-like domain with a tissue inhibitor of metalloproteinases (TIMP) is a major part of the regulatory mechanisms of gelatinases. To investigate the interaction of the hemopexin-like domain of gelatinase B (92-Pex) and TIMP-1, we expressed the individual domain in Pichia pastoris. The active refolded domain was purified by ion exchange chromatography and gel filtration. We investigated the formation of the 92-Pex/TIMP-1 complex by surface plasmon resonance (SPR). The dissociation constant Kd was calculated to be 0.86 nM. Analogous to the complex of the hemopexin-like domain of gelatinase A and TIMP-2 (Olson, M. W. et al., 1997), the binding curves of the 92-Pex/TIMP-1 complex were best fitted with a monophasic model.
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PMID:Kinetic analysis of the binding of hemopexin-like domain of gelatinase B cloned and expressed in Pichia pastoris to tissue inhibitor of metalloproteinases-1. 1470 83

Autoimmune diseases are characterized by inflammation and by the development and maintenance of antibodies and T lymphocytes against "self" antigens. Although the etiology of these diseases is unknown, they have a number of cellular and molecular mechanisms in common. Pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), are upregulated and activate the inflammatory process. Chemokines recruit and activate leukocytes to release proteases, including matrix metalloproteinases (MMPs). These proteases degrade proteins into remnant fragments, which often constitute immunodominant epitopes. Either by direct loading into major histocompatibility complex (MHC) molecules or after classical antigen uptake, processing and MHC presentation, these remnant epitopes are presented to autoreactive T lymphocytes. Also, posttranslationally modified remnant peptides may stimulate B cells to produce autoantibodies. This forms the basis of the "Remnant Epitopes Generate Autoimmunity" (REGA) model. We have documented evidences for this model in multiple sclerosis (MS), rheumatoid arthritis (RA) and diabetes, which are summarized here. Furthermore, three topics will be addressed to illustrate the importance of glycobiology in the pathogenesis of autoimmune diseases. In MS, gelatinase B or MMP-9 is a pathogenic glycoprotein of which the sugars contribute to its interactions with the tissue inhibitor of metalloproteinases-1 (TIMP-1) and thus assist in the determination of the enzyme activity. In RA, gelatinase B cleaves denatured type II collagen into remnant epitopes, some of which constitute immunodominant glycopeptides. This implies that immunodominant epitope scanning experiments should preferably be done with natural posttranslationally modified glycopeptides, rather than with unmodified (synthetic) peptides. Sugars can also be used as molecular probes to induce autoimmune diseases. One of the best examples is the induction of acute pancreatitis, insulitis and diabetes by streptozotocin. In addition, gelatinase B is upregulated in pancreatitis and cleaves insulin. The most efficient cleavage by gelatinase B leads to a major insulin remnant epitope.
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PMID:Remnant epitopes generate autoimmunity: from rheumatoid arthritis and multiple sclerosis to diabetes. 1471 89

Local disruption of the integrity of both the myoepithelial cell layer and the basement membrane is an indispensable prerequisite for the initiation of invasion and the conversion of human breast ductal carcinoma in situ (DCIS) to infiltrating ductal carcinoma (IDC). We previously reported that human endometase/matrilysin-2/matrix metalloproteinase (MMP) 26-mediated pro-gelatinase B (MMP-9) activation promoted invasion of human prostate carcinoma cells by dissolving basement membrane proteins (Y. G. Zhao et al., J. Biol. Chem., 278: 15056-15064, 2003). Here we report that tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-4 are potent inhibitors of MMP-26, with apparent K(i) values of 1.6 and 0.62 nM, respectively. TIMP-2 and TIMP-4 also inhibited the activation of pro-MMP-9 by MMP-26 in vitro. The expression levels of MMP-26, MMP-9, TIMP-2, and TIMP-4 proteins in DCIS were significantly higher than those in IDC, atypical intraductal hyperplasia, and normal breast epithelia adjacent to DCIS and IDC by immunohistochemistry and integrated morphometry analysis. Double immunofluorescence labeling and confocal laser scanning microscopy revealed that MMP-26 was colocalized with MMP-9, TIMP-2, and TIMP-4 in DCIS cells. Higher levels of MMP-26 mRNA were also detected in DCIS cells by in situ hybridization.
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PMID:Endometase/matrilysin-2 in human breast ductal carcinoma in situ and its inhibition by tissue inhibitors of metalloproteinases-2 and -4: a putative role in the initiation of breast cancer invasion. 1474 73


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